Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease worldwide. It is caused by mutations in the inflammasome adaptor Pyrin, but how FMF mutations alter signaling in FMF patients is unknown. Herein, we establish Clostridium difficile and its enterotoxin A (TcdA) as Pyrin-activating agents and show that wild-type and FMF Pyrin are differentially controlled by microtubules. Diverse microtubule assembly inhibitors prevented Pyrin-mediated caspase-1 activation and secretion of IL-1β and IL-18 from mouse macrophages and human peripheral blood mononuclear cells (PBMCs). Remarkably, Pyrin inflammasome activation persisted upon microtubule disassembly in PBMCs of FMF patients but not in cells of patients afflicted with other autoinflammatory diseases. We further demonstrate that microtubules control Pyrin activation downstream of Pyrin dephosphorylation and that FMF mutations enable microtubule-independent assembly of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) micrometer-sized perinuclear structures (specks). The discovery that Pyrin mutations remove the obligatory requirement for microtubules in inflammasome activation provides a conceptual framework for understanding FMF and enables immunological screening of FMF mutations.

We investigated the role of the child's pain catastrophizing in explaining (1) children's self-reported tendency to verbally share their pain experience with others and (2) different dimensions of pain expression, as described by the mother and the father, including non-verbal and verbal communicative pain behaviour and protective pain behaviour. Participants were school children, children with chronic or recurrent pain, and their parents. The results showed that: (1) Pain catastrophizing was associated with children's greater self-acknowledged tendency to verbally share their pain experience with others. (2) Mothers and fathers perceived highly catastrophizing children to be more communicative about their pain. (3) The role of pain catastrophizing in the child's verbal sharing of pain experiences and in explaining expressive behaviour as rated by parents did not differ between the school children and children with recurrent and chronic pain. (4) Nevertheless, findings indicated marked differences between school children and the clinical sample. Children of the clinical sample experienced more severe pain, more pain catastrophizing, more protective pain behaviour, but less verbal communications about their pain. These results further corroborate the position that catastrophic thoughts about pain have interpersonal consequences. Findings are discussed in terms of the possible functions and effects upon others of pain catastrophizing and associated categories of pain behaviour.

Given the high prevalence of masked hypertension, ABPM should be performed in all pediatric LT recipients. Systolic and diastolic hypertension is associated with TAC C0; therefore, children with a higher target TAC C0 require a more intensive blood pressure surveillance.

Our findings indicate that child and parental PF are resilience factors and that pain acceptance buffers the negative impact of pain intensity. Implications for psychosocial interventions that target (pain-specific) PF in children and parents are discussed.

Background and objectiveFamilial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease (AID) worldwide. The disease is caused by mutations in the MEFV gene encoding the inflammasome sensor Pyrin. Clinical diagnosis of FMF is complicated by overlap in symptoms with other diseases, and interpretation of genetic testing is confounded by the lack of a clear genotype–phenotype association for most of the 340 reported MEFV variants. In this study, the authors designed a functional assay and evaluated its potential in supporting FMF diagnosis.MethodsPeripheral blood mononuclear cells (PBMCs) were obtained from patients with Pyrin-associated autoinflammation with an FMF phenotype (n=43) or with autoinflammatory features not compatible with FMF (n=8), 10 asymptomatic carriers and 48 healthy donors. Sera were obtained from patients with distinct AIDs (n=10), and whole blood from a subset of patients and controls. The clinical, demographic, molecular genetic factors and other characteristics of the patient population were assessed for their impact on the diagnostic test read-out. Interleukin (IL)-1β and IL-18 levels were measured by Luminex assay.ResultsThe ex vivo colchicine assay may be performed on whole blood or PBMC. The functional assay robustly segregated patients with FMF from healthy controls and patients with related clinical disorders. The diagnostic test distinguished patients with classical FMF mutations (M694V, M694I, M680I, R761H) from patients with other MEFV mutations and variants (K695R, P369S, R202Q, E148Q) that are considered benign or of uncertain clinical significance.ConclusionThe ex vivo colchicine assay may support diagnosis of FMF and functional subtyping of Pyrin-associated autoinflammation.